Background: Acute pancreatitis (AP) is a common acute abdominal disease in clinical practice. Severe AP (SAP) usually progresses rapidly, leading to systemic inflammatory response syndrome, multiple organ failure, and even death. Early identification of severe cases with timely and effective treatment can improve patient's prognosis and reduce mortality. Aims: To explore the value of single and combined detection of C-reactive protein (CRP), interleukin-6 (IL-6) and procalcitonin (PCT) in the early assessment of severity of AP. Methods: A total of 472 AP patients hospitalized in Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine from January 2018 to December 2020 were enrolled retrospectively. The laboratory data within 48 h of admission were extracted, and the patients were allocated into mild AP (MAP) group and SAP group (including moderately severe and severe AP) according to the 2012 revised Atlanta classification. The differences of CRP, IL-6 and PCT between the two groups were statistically analyzed, and the value of single and combined detection of the three indicators for predicting the disease severity was determined by ROC curve analysis. Results: The levels of CRP, IL-6 and PCT in SAP group were significantly higher than those in MAP group (all P< 0.05). ROC curve analysis revealed that the area under the curve (AUC) of single, two and three indicators combined for predicting SAP was all higher than 0.7, which represented a moderately diagnostic accuracy. Three indicators combined demonstrated the highest diagnostic accuracy (AUC=0.826); with an optimal cut-off value, the sensitivity and specificity were 71.4% and 79.3%, respectively. Conclusions: CRP, IL-6 and PCT are meaningful in early assessment of severity of AP. The overall diagnostic value of combined detection of three indicators is superior to single and two indicators combination in predicting SAP.